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In the lab today and possibly the surgical suite tomorrow, this technique drives expanding medical applications
Advancing the accuracy of tools used in medicine promises better health for everyone, and mass spectrometry (MS) is poised to improve healthcare—from drug development to disease diagnosis. Maximizing these advances in medicine will take more work. “Currently, there are many obstacles facing the field of clinical mass spectrometry,” says Y. Victoria Zhang, director of the clinical mass spectrometry and toxicology laboratory at the University of Rochester Medical Center (Rochester, N.Y.) and founding chair of the American Association of Clinical Chemistry’s Mass Spectrometry and Separation Sciences Division (AACC MSSS). “For instance, there are significant knowledge gaps about MS in the community; the technology is very labor intensive, time consuming and costly; and the nature of laboratory-developed tests for mass spec assays results in barriers in developing and implementing these assays in clinical practices.”
The influenza virus shown here can be characterized using mass spectrometry. (Image courtesy of the U.S. Centers for Disease Control and Prevention.)To address those challenges, the AACC MSSS targets three areas. The first is education, which it improves, Zhang says, “through developing targeted programs on the technology, its clinical applications, financial considerations in bringing this technology to clinical practices, as well as training for laboratory technologists.” It also supports an online certificate program in the clinical applications of MS. Second, this division identifies “the gaps and challenges in the field of clinical mass spectrometry and mobilizes community experts to provide solutions and guidance for the new development of the next generation of mass spectrometry,” Zhang explains. Examples of this include the role of automation, miniaturization of MS and tissue imaging. Third, experts in academia, industry, regulatory bodies and the community are connected to discuss these challenges and exchange ideas to move the field forward. “Lack of automation for both sample preparation and data reporting and FDA regulations on laboratory-developed tests are great examples that require multiple parties to work together to come up with better solutions for the field,” Zhang says. “The MSSS division provides that platform for team efforts on viable solutions to advance the clinical applications of MS—all for the betterment of patient care.”
MS is already used in various clinical applications, often because of its breadth. “Mass spectrometers are good at both small- and large-molecule analysis,” says Bradley Hart, strategic director, LSMS translational research/ IVD/toxicology for Thermo Fisher Scientific, headquartered in Waltham, Mass. “In the clinical laboratory some of the most common analytes include drugs of abuse, immunosuppressants, Vitamin D, IGF-1, insulin and parathyroid hormone and testosterone.”
The triple-quad LCMS-8050 CL from Shimadzu is classified as an IVD medical device. (Image courtesy of Shimadzu.)MS can be used virtually anywhere in laboratory medicine, says Donald Mason, scientific affairs manager at Waters Corp in Milford, Mass., citing newborn screening for inborn metabolic disorders, toxicology and endocrinology as examples. Some uses are not new at all. Scott Kuzdzal, general manager of marketing at Shimadzu Scientific Instruments in Columbia, Md., points out that gas chromatography has been used with MS in the clinic for decades to analyze volatile substances in blood. Even more clinical uses of MS lie ahead.
New opportunities
Despite the challenges to using MS in the clinic, the technology continues to evolve. “There are many recent advances in using MS in clinical applications that are very exciting,” Zhang says. These include using high-resolution MS in drug screening and new assay developments to analyze proteins or peptides. Zhang also points out the “booming applications of MALDI-TOF (matrix-assisted laser desorption ionization-time of flight) in microorganism identification.”
Moving MS ahead in the clinic comes from technological advances in some cases, but, as Zhang explains, “Most of the technologies have existed and [have] been used in research for a long time. …What I think is more important is the combination of the technology and the clinical challenges.” Experts in the field know where MS delivers clinical advantages and where it faces challenges. Zhang says, “I think we are at the pivotal point for the MS technology to make a revolutionary difference in clinical applications, and there will be more exciting advances coming up in the near future of the MS in clinical practices.”
Various features will drive this revolution. As Hart says of MS, “Its speed, definitive identification and the increasing ease-of-use of mass spec-based tests have driven the technology from the domain of complexity to an instrument nearly anyone in the laboratory can use.” He adds, “As our industry continues to innovate and make instruments that are powerful, easy to approach and reliable, we expect the adoption of the technology to increase even more.”
Mass spectrometry is a workhorse analytical technology in the clinical laboratory for diagnostic and therapeutic drug monitoring purposes. (Image courtesy of Waters Corp.)Any technology used in a clinical setting benefits from higher throughout. That speed also increases by making the technology easier to use, which reduces setup time. Hart says, “The [Thermo Scientific] Endura MD mass spectrometer and Prelude MD HPLC use CLIA-compliant ClinQuan MD software with simple, step-by-step processes for method selection, building sample lists, running samples and performing daily maintenance, quality control and reporting.”
The devices that deliver samples to an MS also impact the speed. Hart says, “The Prelude LX-4 MD HPLC brings the productivity of up to four HPLC channels to a single mass spectrometer, so you can run up to four times the samples.”
MS platforms
As MS moves deeper into the clinical space, some vendors are offering platforms certified for this use, which means handling regulatory requirements.
“Thermo Fisher Scientific’s new suite of products, the ‘MD’-series mass spectrometer, liquid chromatography, sample clean up and the software that unites them were specifically designed for use in the clinical laboratory,” Hart says. “Specific features include the ability to measure a wide range of compounds and matrices, minimization of background noise by removing more solvent vapor and blocking neutrals and five orders of dynamic range for accurate quantitation of low-concentration or limited samples.” The MD instruments are also listed as Class I general-purpose medical devices for use as components in laboratory-developed tests for analyzing patient samples.
Many of the devices from Waters are also listed as Class I in vitro diagnostic (IVD) medical devices; these include the ACQUITY TQD, Xevo TQD and Xevo TQ-S tandem quadrupole mass spectrometers. In China, the ACQUITY UPLC I-Class/Xevo TQ-S mass spectrometer and ACQUITY TQD have been approved for newborn screening.
These platforms are suitable for a range of uses. “Tandem quad MS could be used in pharma, environmental testing and clinical,” says Mason. “They are not purpose-built for the clinical market.” That will change in the future. “Purpose-built LC/MS for clinical labs is on the horizon,” Mason says. Even farther ahead, MS might one day be used for tissue imaging or guiding surgeons resecting a tumor, but such applications must await definitive, objective, molecular-level information for well-informed, accurate, realtime decisions to be made.
Shimadzu also offers a family of MS platforms that are classified as IVD medical devices, including the LCMS-8040 CL and LCMS-8050 CL, which are triple-quad LC/MS/MS devices. These ultrafast instruments increase throughput and allow positive and negative analytes to be monitored in a single run. Shimadzu is also working on a new clinical laboratory automation module, which, according to Kuzdzal, “integrates sample preparation steps such as liquid sample/reagent dispensing, shaking, filtration and heating, and automatically transfers samples directly into the LC/MS/MS.”
Developing assays in academics
At the University of California, San Diego School of Medicine’s toxicology laboratory, director Robert Fitzgerald and his colleagues use LC and tandem MS to identify and quantify small molecules in the clinical laboratory. Primarily, they develop assays for drugs-of-abuse testing and analysis of 25-hydroxyvitamin D. Fitzgerald says, “We are also developing assays for steroids, broad-spectrum drug screens and heavy metals analysis.”
Special care must be taken to develop a clinical application, because lives are at stake. “Assuming you have a laboratory with appropriate instrumentation, the initial challenge is method validation,” Fitzgerald says. “The other major challenges are instrument connectivity and automation.” He adds, “Interfaces between the mass spectrometer, the laboratory information system and any sample preparation automation require significant on-site expertise.”
The work from Fitzgerald’s lab demonstrates the incentive to push MS even deeper into the clinical world. We may not see an MS system in our local physician’s office anytime soon, but this technology already improves healthcare.
Mike May is a freelance writer and editor living in Ohio. He can be reached at [email protected].